PROJECTSUMMARY Oneofthehallmarksofcanceristhereprogrammingofmetabolismfromoxidativephosphorylationthattakes placeinmitochondriatoglycolysis,regardlessofoxygenavailability.Thisso-called?Warburgeffect?isan importantdiseasedriverandhallmarkofpooroutcome.However,itisnowclearthatthereisgreater complexityintumormetabolism,asmitochondriacontinuetoplayanimportantroleinthebioenergeticsof transformedcells,andfuelkeycancertraitsofproliferation,drugresistance,stemnessandinvasion.Work supportedbyCA78801demonstratedthatapoolofthecancergene,survivinpresentinmitochondriaoftumor cellsmaintainedoxidativephosphorylationmetabolism.Inturn,energyproducedviathispathwayenabledthe subcellularmovementofmitochondriatothecorticalcytoskeletonoftumorcells,fuelingmembrane lamellipodiadynamics,turnoveroffocaladhesioncomplexes,andsustainedphosphorylationofcellmotility kinases.Together,thisledtoheightenedtumorchemotaxis,invasionandmetastasis,invivo.Publishedinthe peer-reviewedliterature(SciSignal8:389,2015;?PNAS112:8638,2015),anddiscussedinthreeinvitedreview articles(PharmacolRev102:42,2015;?CellCycle14:20,2015;?ClinCancerRes22:540,2016),theseresults supportedamodelofspatiotemporalmitochondrialbioenergeticsasarequirementoftumorcellmotility, invasionandmetastasis.Infollow-upstudies,wehavenowfoundthatchangesinmitochondrialsizeand shape,knownasdynamics,aswellasmechanismsoforganellequalitycontrol,suchasmitophagy,are essentialregulatorsofthispathway.Specifically,conditionsthatimpairmitochondrialfusion,promote exaggeratedmitochondrialfragmentation(fission),oractivatemitophagysuppressmitochondrialtraffickingand blocktumorcellmotility.Therefore,thehypothesisthatorganelledynamicsandqualitycontrolregulate spatiotemporalmitochondrialbioenergeticsandmetastaticcompetencecanbeformulated,andwillconstitute thefocusofthepresentrevisionapplication.IncontinuitywiththeobjectivesofCA78810,thefirstspecificaim willelucidatehowmitochondrialfusionandfissionregulateorganellemovements,membrane-actindynamics andthemachineryoftumorcellmotility.ThesecondspecificaimwillfocusonParkin-dependentand? independentmitophagy,andanovelroleoftheFUNDC2moleculeasnovel?metastasissuppressors?, regulatingmitochondrialrecruitmenttothecorticalcytoskeletonandthebioenergeticsoftumorcellinvasion. Asdynamicsandqualitycontrolaretheprimaryeffectorsofmitochondrialheterogeneity,thesestudiesarean idealmatchtotheobjectiveofthePQ5Program,willconclusivelyansweritsoverarchingquestionofhowdoes mitochondrialheterogeneityinfluencetumorigenesisorprogression,anduncoveractionabletherapeutic targetstolimitdiseasedisseminationintheclinic.